The present invention relates to L-glutamate uptake inhibitors, and more specifically .beta.-hydroxyaspartic acid derivatives which have an inhibitory effect on the glutamate uptake activity of L-glutamate transporters.
The present compounds provide footholds for developing inhibitors of L-glutamate transporters to take up glutamate and for the treatment of neuropathies or neurodegenerative diseases such as epilepsy, Huntington's diseases, amyotrophic lateral sclerosis (ALS), and Alzheimer's diseases.
L-Glutamate has been known as an excitatory neurotransmitter in the mammalian central nervous system, which not only induces rapid neurotransmission between synapses but also participates in high-order and complex physiological processes such as memory or learning. Excitatory neurotransmission between synapses begins with release of glutamate from presynapses and terminates with rapid uptake of glutamate by high-affinity glutamate transporters present in presynapses and glial cells from synaptic clefts (Attwaell, D. and Nicholls, D., TIPS 68-74, 1991).
In certain genetic neurodegenerative diseases, a decrease of sodium-dependent glutamate uptake activity has been reported in the brains of some patients (Rothstein, J. D. et al., N. Eng. J. Med. 326, 1464-1468, 1992). This attracted the attention of researchers to the function of glutamate transporters in connection with these diseases, especially to the expression of the function and inhibition thereto.
Prior studies on glutamate transporters have concentrated on synaptosomes prepared from the brain or membrane samples prepared from kidney or small intestine. Approaches on the basis of molecular biology have also been made since 1992 when cDNAs of sodium-dependent high-affinity glutamate transporters were cloned (Pines, G. et al., Nature 360, 464-467, 1992; Storck, T. et al., Proc. Natl. Acad. Sci. USA, 89, 10955-10959, 1992; Kanai, Y. et al., Nature 360, 467-471, 1992). More recently, human glutamate transporter genes have been cloned and grouped into subtypes EAAT1 to 5 (Arriza, J. L. et al., J. Neurosci. 14, 5559-5569, 1994; Arriza, J. L. et al., Nature, 375, 599-603, 1995; Arriza, J. L. et al., Proc. Natl. Acad. Sci. 94, 4155 1997).
Up to the present, glutamate uptake inhibitors such as threo-.beta.-hydroxyaspartate and CCG-III [(2S, 1'S, 2'R)-2-(2-carboxycyclopropyl)glycine] have been discovered as a result of the screening for glutamate uptake inhibitors by way of synaptosomes. These compounds are antagonists which by themselves are taken up as substrates by transporters, and hence, competitively inhibit glutamate uptake.
On the other hand, electrophysiological studies have shown that glutamate uptake inhibitors such as kainic acid and dihydrokainic acid act as a blocker rather than a competitive substrate because they inhibit glutamate uptake without being taken up by transporters. These compounds have also been shown to selectively act on EAAT2 (GLT-1 type) among the five EAAT subtypes (Arriza, J. L. et al., J. Neurosci. 14, 5559-5569, 1994). However, these compounds also act on ion channel-type glutamate receptors to induce a strong neuroexcitation.
Under these circumstances, there is a demand for the development of various inhibitors for glutamate transporters, especially those acting as a blocker, in order to elucidate relations between glutamate transporters and neuropathies or neurodegenerative diseases such as epilepsy, Huntington's diseases, amyotrophic lateral sclerosis (ALS), and Alzheimer's diseases.